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  • 1
    Language: English
    In: Respiratory Research, 01 July 2010, Vol.11(1), p.93
    Description: Abstract Background Legionella pneumophila is an important causative agent of severe pneumonia in humans. Human alveolar epithelium and macrophages are effective barriers for inhaled microorganisms and actively participate in the initiation of innate host defense. The beta defensin-3 (hBD-3), an antimicrobial peptide is an important component of the innate immune response of the human lung. Therefore we hypothesize that hBD-3 might be important for immune defense towards L. pneumophila. Methods We investigated the effects of L. pneumophila and different TLR agonists on pulmonary cells in regard to hBD-3 expression by ELISA. Furthermore, siRNA-mediated inhibition of TLRs as well as chemical inhibition of potential downstream signaling molecules was used for functional analysis. Results L. pneumophila induced release of hBD-3 in pulmonary epithelium and alveolar macrophages. A similar response was observed when epithelial cells were treated with different TLR agonists. Inhibition of TLR2, TLR5, and TLR9 expression led to a decreased hBD-3 expression. Furthermore expression of hBD-3 was mediated through a JNK dependent activation of AP-1 (c-Jun) but appeared to be independent of NF-κB. Additionally, we demonstrate that hBD-3 elicited a strong antimicrobial effect on L. pneumophila replication. Conclusions Taken together, human pulmonary cells produce hBD-3 upon L. pneumophila infection via a TLR-JNK-AP-1-dependent pathway which may contribute to an efficient innate immune defense.
    Keywords: Medicine
    ISSN: 1465-9921
    E-ISSN: 1465-993X
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  • 2
    Language: English
    In: Intensive Care Medicine, 2004, Vol.30(3), pp.430-436
    Description: Byline: Peter Schellongowski (1), Michael Benesch (2), Thomas Lang (2), Friederike Traunmuller (1), Christian Zauner (3), Klaus Laczika (1), Gottfried J. Locker (1), Michael Frass (1), Thomas Staudinger (1) Keywords: Scoring; Cancer; Critical care; Acute Physiology and Chronic Health Evaluation (APACHE) II; Simplified Acute Physiology Score (SAPS) II; Mortality Probability Model II Abstract: Objective To compare three scoring systems, the Acute Physiology and Chronic Health Evaluation (APACHE) II, the Simplified Acute Physiology Score (SAPS) II and a modified Mortality Probability Model II (ICU cancer mortality model, ICMM) for their prognostic value for mortality during hospital stay in a group of cancer patients admitted to a medical ICU. Design Prospective cohort study. Setting Medical ICU of a tertiary care hospital. Patients Two hundred forty-two consecutive cancer patients admitted to the ICU. Measurements and results Variables included in APACHE II, SAPS II and the ICMM scores as well as demographic data were assessed during the first 24 h of stay in the ICU. Hospital mortality was measured it was 44%. Calibration for all three scoring systems was acceptable, SAPS II yielded a significantly superior discrimination between survivors and non-survivors. The areas under the receiver operating characteristic curves were 0.776 for APACHE II, 0.825 for SAPS II and 0.698 for the ICMM. Conclusion The SAPS II was superior to APACHE II and ICMM. The newly developed ICMM does not improve mortality prediction in critically ill cancer patients. Author Affiliation: (1) Department of Internal Medicine I, University of Vienna, Waehringer Guertel 18--20, 1090, Vienna, Austria (2) Institute for Medical Statistics, University of Vienna, Schwarzspanierstrasse 17, 1090, Vienna, Austria (3) Department of Internal Medicine IV, University of Vienna, Waehringer Guertel 18--20, 1090, Vienna, Austria Article History: Registration Date: 01/01/2003 Received Date: 03/04/2003 Accepted Date: 29/09/2003 Online Date: 04/11/2003
    Keywords: Scoring ; Cancer ; Critical care ; Acute Physiology and Chronic Health Evaluation (APACHE) II ; Simplified Acute Physiology Score (SAPS) II ; Mortality Probability Model II
    ISSN: 0342-4642
    E-ISSN: 1432-1238
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  • 3
    Language: English
    In: Pharmaceutical research, May 2013, Vol.30(5), pp.1380-99
    Description: To investigate antibody stability and formation of modified species under upstream processing conditions. The stability of 11 purified monoclonal human IgG1 and IgG4 antibodies, including an IgG1-based bispecific CrossMab, was compared in downscale mixing stress models. One of these molecules was further evaluated in realistic bioreactor stress models and in cell culture fermentations. Analytical techniques include size exclusion chromatography (SEC), turbidity measurements, cation exchange chromatography (cIEX), dynamic light scattering (DLS) and differential scanning calorimetry (DSC). Sensitivity in downscale stress models varies among antibodies and results in formation of high molecular weight (HMW) aggregates. Stability is increased in cell culture medium and in bioreactors. Media components stabilizing the proteins were identified. Extensive chemical modifications were detected both in stress models as well as during production of antibodies in cell culture fermentations. Protective compounds must be present in chemically defined fermentation media in order to stabilize antibodies against the formation of HMW aggregates. An increase in chemical modifications is detectable in bioreactor stress models and over the course of cell culture fermentations; this increase is dependent on the expression rate, pH, temperature and fermentation time. Consequently, product heterogeneity increases during upstream processing, and this compromises the product quality.
    Keywords: Antibodies, Monoclonal -- Chemistry ; Immunoglobulin G -- Chemistry
    ISSN: 07248741
    E-ISSN: 1573-904X
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  • 4
    In: Neurology, 2016, Vol.87(2), pp.168-177
    Description: OBJECTIVE:: This was a longitudinal single-center cohort study to comprehensively explore multimodal progression markers for Parkinson disease (PD) in patients with recently diagnosed PD (n = 123) and age-matched, neurologically healthy controls (HC; n = 106). METHODS:: Thirty tests at baseline and after 24 months covered nonmotor symptoms (NMS), cognitive function, and REM sleep behavior disorder (RBD) by polysomnography (PSG), voxel-based morphometry (VBM) of the brain by MRI, and CSF markers. Linear mixed-effect models were used to estimate differences of rates of change and to provide standardized effect sizes (d) with 95% confidence intervals (CI). RESULTS:: A composite panel of 10 informative markers was identified. Significant relative worsening (PD vs HC) was seen with the following markers: the Unified Parkinsonʼs Disease Rating Scale I (d 0.39; CI 0.09–0.70), the Autonomic Scale for Outcomes in Parkinsonʼs Disease (d 0.25; CI 0.06–0.46), the Epworth Sleepiness Scale (d 0.47; CI 0.24–0.71), the RBD Screening Questionnaire (d 0.44; CI 0.25–0.64), and RBD by PSG (d 0.37; CI 0.19–0.55) as well as VBM units of cortical gray matter (d −0.2; CI −0.3 to −0.09) and hippocampus (d −0.15; CI −0.27 to −0.03). Markers with a relative improvement included the Nonmotor Symptom (Severity) Scale (d −0.19; CI −0.36 to −0.02) and 2 depression scales (Beck Depression Inventory d −0.18; CI −0.36 to 0; Montgomery-Åsberg Depression Rating Scale d −0.26; CI −0.47 to −0.04). Unexpectedly, cognitive measures and select laboratory markers were not significantly changed in PD vs HC participants. CONCLUSIONS:: Current CSF biomarkers and cognitive scales do not represent useful progression markers. However, sleep and imaging measures, and to some extent NMS, assessed using adequate scales, may be more informative markers to quantify progression.
    Keywords: Neurologi ; Neurology ; Psykiatri ; Psychiatry ; Geriatrik ; Geriatrics;
    ISSN: 0028-3878
    E-ISSN: 1526632X
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  • 5
    In: Neurology, 2013, Vol.81(14), pp.1226-1234
    Description: OBJECTIVE:: To determine nonmotor signs (NMS) and evaluate the utility of several diagnostic tools in patients with de novo Parkinson disease (PD). METHODS:: This is a large single-center study of the DeNoPa cohort, including frequency-matched healthy controls. This study covers motor signs, NMS, and a combination of diagnostic tests including olfactory testing, transcranial sonography of substantia nigra (TCS), and polysomnography (PSG). We report the frequency and characteristics of NMS and the outcomes of nonmotor tests at the time of diagnosis. RESULTS:: Cross-sectional analyses of baseline investigations identified significant differences in the NMS Questionnaire (NMSQuest) and the Scopa-AUT Gastrointestinal score in 159 drug-naïve PD patients vs 110 controls. In addition, patients with PD showed reduced olfactory function, hyperechogenicity on TCS, and higher frequency of REM sleep behavior disorder (RBD). In exploring predictive markers, we found that the combination of several investigations, i.e., the NMSQuest, Scopa-AUT Gastrointestinal score, and Smell Identification Test reached an area under the receiver operating characteristic curve (AUC) of 0.913 (95% confidence interval [CI] 0.878–0.948). With the addition of serum cholesterol and mean heart rate values, the AUC value reached 0.919 (95% CI 886–0.953); when TCS and PSG were added, the AUC increased to 0.963 (95% CI 0.943–0.982). CONCLUSIONS:: We show feasibility and utility of standardized data acquisition in a large, single-center cohort of patients with de novo PD and matched healthy controls. The baseline results from our prospective investigations reached a value of 〉0.9 sensitivity and specificity for biological markers when we added routine laboratory investigations and quantified nonmotor features including sleep.
    Keywords: Substantia Nigra ; Inventories ; Neurodegenerative Diseases ; Sleep (Rem) ; Movement Disorders ; Parkinson'S Disease ; Heart Rate ; Cholesterol ; Biomarkers ; Data Acquisition ; Olfaction ; Neurology & Neuropathology;
    ISSN: 0028-3878
    E-ISSN: 1526632X
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  • 6
    Language: English
    In: Blood, 19 July 2018, Vol.132(3), pp.307-320
    Description: Heat shock protein 90 (HSP90) stabilizes many client proteins, including the BCR-ABL1 oncoprotein. BCR-ABL1 is the hallmark of chronic myeloid leukemia (CML) in which treatment-free remission (TFR) is limited, with clinical and economic consequences. Thus, there is an urgent need for novel therapeutics that synergize with current treatment approaches. Several inhibitors targeting the N-terminal domain of HSP90 are under investigation, but side effects such as induction of the heat shock response (HSR) and toxicity have so far precluded their US Food and Drug Administration approval. We have developed a novel inhibitor (aminoxyrone [AX]) of HSP90 function by targeting HSP90 dimerization via the C-terminal domain. This was achieved by structure-based molecular design, chemical synthesis, and functional preclinical in vitro and in vivo validation using CML cell lines and patient-derived CML cells. AX is a promising potential candidate that induces apoptosis in the leukemic stem cell fraction (CD34CD38) as well as the leukemic bulk (CD34CD38) of primary CML and in tyrosine kinase inhibitor (TKI)-resistant cells. Furthermore, BCR-ABL1 oncoprotein and related pro-oncogenic cellular responses are downregulated, and targeting the HSP90 C terminus by AX does not induce the HSR in vitro and in vivo. We also probed the potential of AX in other therapy-refractory leukemias. Therefore, AX is the first peptidomimetic C-terminal HSP90 inhibitor with the potential to increase TFR in TKI-sensitive and refractory CML patients and also offers a novel therapeutic option for patients with other types of therapy-refractory leukemia because of its low toxicity profile and lack of HSR.
    Keywords: Animals–Chemistry ; Antineoplastic Agents–Pharmacology ; Binding Sites–Drug Effects ; Biomarkers, Tumor–Drug Effects ; Cell Cycle–Drug Effects ; Cell Line, Tumor–Antagonists & Inhibitors ; Cell Survival–Chemistry ; Disease Models, Animal–Antagonists & Inhibitors ; Drug Resistance, Neoplasm–Chemistry ; Fusion Proteins, Bcr-Abl–Metabolism ; Hsp90 Heat-Shock Proteins–Drug Effects ; Heat-Shock Response–Chemistry ; Humans–Pharmacology ; Imatinib Mesylate–Drug Therapy ; Leukemia, Myelogenous, Chronic, BCR-Abl Positive–Metabolism ; Mice–Chemistry ; Models, Molecular–Pharmacology ; Molecular Conformation–Drug Effects ; Molecular Structure–Drug Effects ; Protein Binding–Drug Effects ; Protein Interaction Domains and Motifs–Drug Effects ; Protein Kinase Inhibitors–Drug Effects ; Protein Multimerization–Drug Effects ; Spectrum Analysis–Drug Effects ; Structure-Activity Relationship–Drug Effects ; Xenograft Model Antitumor Assays–Drug Effects ; Abridged ; Antineoplastic Agents ; Biomarkers, Tumor ; Hsp90 Heat-Shock Proteins ; Protein Kinase Inhibitors ; Imatinib Mesylate ; Fusion Proteins, Bcr-Abl;
    ISSN: 00064971
    E-ISSN: 1528-0020
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  • 7
    Language: English
    In: International Journal of Oncology, August 2011, Vol.39(2), pp.515-520
    Description: We performed this study in order to evaluate the impact of the chemokine CXCL12 and its single-nucleotide polymorphism (SNP) rs1801157 on clinicopathological parameters and survival in patients undergoing surgery for esophagogastric cancer. The expression pattern of CXCL12 and its polymorphisms were analyzed by RT-PCR and PCR-RFLP in 69 consecutive fresh-frozen samples of human esophagogastric junction and gastric adenocarcinomas and statistically analyzed. Expression of the CXCL12 (SNP rs1801157) polymorphisms GA/AA significantly correlated with distant metastasis (P=0.026), but not with prognosis. However, CXCL12 expression was not significantly associated with the tumor infiltration depth, lymphatic metastasis and grading. As CXCL12 polymorphisms mediate tumor cell dissemination in esophagogastric cancer, they could represent a marker indicating advanced disease. Antagonists targeting the CXCL12/ CXCR4 axis may be a novel therapeutic option in this entity.
    Keywords: Medicine;
    ISSN: 1019-6439
    E-ISSN: 17912423
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  • 8
    Language: German
    In: Klinische Monatsblatter fur Augenheilkunde, July 2017, Vol.234(7), pp.891-893
    Description: There is a growing interest in quality measurement in the healthcare sector. Hospitals in Germany are obligated to participate in measures for external quality assurance and they must establish an internal quality management system. In addition to the legal requirements, measurement of quality is also possible with routine data. Suitable sources are the ICD system or unstandardized information from treatment documentation. The selection of suitable quality indicators is necessary to interpret the data. Complications or achievement of surgical objectives can be suitable quality indicators. Analysis of procedures or the assessment of waiting time are also possible indicators. Our first data concerning waiting time show that with increasing use of an electronic patient guidance system, the waiting time decreased in our outpatient department. Assessment of quality indicators from routine data enables a continuous measurement of quality over a long period. Measures to increase quality can easily be checked. Routine data also provide the possibility to participate in a public reporting of quality indicators.
    Keywords: Delivery of Health Care -- Standards ; Hospital Records -- Standards ; Ophthalmology -- Standards ; Quality Assurance, Health Care -- Standards ; Quality Indicators, Health Care -- Standards
    ISSN: 00232165
    E-ISSN: 1439-3999
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  • 9
    Language: English
    In: European Archives of Oto-Rhino-Laryngology, 2018, Vol.275(10), pp.2507-2513
    Description: To access, purchase, authenticate, or subscribe to the full-text of this article, please visit this link: http://dx.doi.org/10.1007/s00405-018-5105-2 Byline: Kerstin Stahr (1), Laura Holtmann (1), Anke Schluter (1), Friederike Kaster (1), Michael Oeverhaus (2), Stephan Lang (1), Anja Eckstein (2), Stefan Mattheis (1) Keywords: Graves' orbitopathy; Orbital decompression; Nasal airflow; Olfactory performance; Surgical outcome Abstract: Purpose To determine the influence of anatomical changes after orbital decompression to nasal function. Methods We examined postoperative nasal function after orbital decompression in patients with GO in a prospective study. 25 patients were enrolled between 2014 and 2016. Sense of smell (Sniffin' Test) and nasal airflow (anterior rhinomanometry) were tested pre- and 6 weeks postoperatively. In addition, postoperative incidence of sinus infections, persistent pressure pain, and infraorbital hypoesthesia were assessed by means of a questionnaire. Results The olfactory performance showed a significant increase (p〈0.05) after surgery, while the nasal airflow significantly decreased (p〈0.05). Acute sinus infection occurred in three, infraorbital sensibility disorders in eight cases within the first 6 weeks after surgery. No persistent pain was recorded. Conclusion We demonstrate that decompression of the medial orbital wall leads to a decrease in nasal airflow, whereof patients should be informed before the procedure. This is most likely due to a medialization of the medial turbinate and the prolapse of orbital content into the nasal cavity. The increase of the olfactory performance is, in our opinion, more likely due to variation within the standard deviation than to anatomical changes. Author Affiliation: (1) 0000 0001 0262 7331, grid.410718.b, Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Essen, Hufelandstr. 55, 45147, Essen, Germany (2) 0000 0001 0262 7331, grid.410718.b, Department of Ophthalmology, University Hospital Essen, Hufelandstr. 55, 45147, Essen, Germany Article History: Registration Date: 21/08/2018 Received Date: 08/06/2018 Accepted Date: 21/08/2018 Online Date: 30/08/2018
    Keywords: Graves’ orbitopathy ; Orbital decompression ; Nasal airflow ; Olfactory performance ; Surgical outcome
    ISSN: 0937-4477
    E-ISSN: 1434-4726
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  • 10
    In: Medicine, 2016, Vol.95(38), pp.e4602-e4602
    Description: ABSTRACT: We aimed to validate the liver fibrosis index FIB-4 as a model for risk stratification of hepatocellular carcinoma development in predominantly non-Asian patients with chronic hepatitis B infection seen at a tertiary referral center in Germany.We retrospectively analyzed 373 adult patients with chronic hepatitis B infection. Patient demographics, hepatitis B markers, antiviral treatment, laboratory parameters, results from liver imaging and histology were recorded. Patients were divided into 2 groups according to their FIB-4 levels and their hazard ratios for developing hepatocellular carcinoma were analyzed adjusted for age, sex, body mass index, alcohol consumption, and antiviral medication.Median follow-up was 8.7 years (range 1–21.3 years), 93% of patients were of non-Asian origin, and 64% were male. Compared with patients with a low FIB-4 (〈1.25) patients with FIB-4 ≥1.25 showed a hazard ratio for incidence of hepatocellular carcinoma of 3.03 (95% confidence interval (CI): 1.24–7.41) and an adjusted hazard ratio of 1.75 (95% CI: 0.64–4.74). Notably, 68% of patients with liver cirrhosis and 68% of those who developed HCC during observation had a low FIB-4 (〈1.25).We could not confirm that a FIB-4 value ≥1.25 is a reliable clinical indicator for incidence of hepatocellular carcinoma in predominantly non-Asian patients with chronic hepatitis B. Further studies in geographically and ethnically diverse populations are needed to prove its utility as a predictive tool.
    Keywords: Medicine;
    ISSN: 0025-7974
    E-ISSN: 15365964
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